The presence of unbuffered acid appears to be an essential contributory factor in the pathogenesis of peptic ulcers such ae gastric ulcer, duodenal ulcer gastritis and the like. Therefore, the treatment of the peptic ulcer has concentrated on the reduction of acidity, that is, an inhibition of gastric acid secretion. In view of this, an H.sub.2 -antagonist such as cimetidine, famotidine, ranitidine and a proton pump inhibitor such as omeprazole have been developed and used clinically as anti-ulcer agents.
Acid secretion by the stomach is carried out by the parietal cells of the gastric epithelium. Histamine, gastrin and acetylcholine directly bind to their respective receptors in a parietal cell that induces a cascade of intracellular events inducing acid secretion. The initial events involve changes in the concentration of intracellular second messengers. Histamine receptor linked to adenylate cyclase influences intracelluar levels of cAMP which causes an increase in protein kinase A activity and cytoplasmic Ca.sup.2+ concentration (hereinafter abbreviated as [Ca.sup.2+ ]i). The occupation of gastrin and muscarinic receptors leads to 1,4,5-inositol triphosphate (hereinafter abbreviated as 1,4,5-IP.sub.3) formation which causes a release of Ca.sup.2+ from intracellular store.
The secretagogue such as histamine, gastrin, or acetylcholine stimulates gastric acid secretion accompanied by dramatic transformation of the parietal cell cytoskeletal structure, rapid changes in enzyme location and activity, and opening of ion channels.
That is, the resting parietal cell contains a collapsed canalicular system and cytoplasmic tubulovesicles contain the gastric proton pump H.sup.+,K.sup.+ -ATPase. Stimulation of parietal cells by those secretagogues induces formation of a dense apical meshwork of intracellular canaliculi packed with long microvilli. The apical membrane surface area increases 5- to 10-fold after stimulation. This increase coincides with the disappearance of the majority of cytoplasmic tubulovesicles seen in a resting parietal cell. The mechanism of this increase in membrane surface area appears to arise from a fusion of tubulovesicles and apical membrane including translocation of H.sup.+,K.sup.+ -ATPase from tubulovesicles in the resting cell to the apical membrane in the stimulated cells. The fusion of tubulovesicles with the apical membrane is directed by cytoskeletal microfilaments composed of actin and other proteins such as myosin. Membrane is recycled back to tubulovesicles as cells return to the resting state, and this process also appears to be mediated by actincontaining microfilaments. The actin mediate H.sup.+,K.sup.+ -ATPase translocation which is an essential and important process in the initiation of gastric acid secretion in parietal cells (Text Book of Gastroenterolgy, J. B. Lippincott Page 246 1991).
The myosin commonly associated with actin and is found in the parietal cell. MLCK is a Ca.sup.2+ -calmodulin dependent enzyme which mediates the phosphorylation of myosin light chain and is considered to play an important role in the regulation of the contractility of actomyosin system, that is, cytoskeletal microfilaments.
With the above mechanism of the gastric acid secretion, an H.sub.2 antagonist blocks the reaction after stimulation due to histamine gastrin or muscarinic receptor activation. Also, a proton pump inhibitor directly inhibits H.sup.+,K.sup.+ -ATPase activity.
However, no suggestion has been made that MLCK inhibitor may inhibit the transformation of a parietal cell to inhibit gastric acid secretion, and the role of myosin and MLCK in the process of gastric acid secretion has never been examined.